The present invention relates to a process for the optical resolution of a key intermediate for preparing pharmacologically active 2,7-substituted octahydro-1H-pyrido[1,2-a]pyrazine derivatives, such as (7S,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido(1,2-a)pyrazine, which are disclosed in U.S. Pat. No. 5,852,031, the contents of which are hereby incorporated by reference. These pyrazine compounds are ligands with specificity for dopamine receptor subtypes, especially the dopamine D4 receptor, within the animal body, and are therefore useful in the treatment of disorders of the dopamine system. The process of the present invention involves resolution of trans-7-(hydroxymethyl)octahydro-2H-pyrido(1,2-a)pyrazine using D-(xe2x88x92) or L-(+)naproxen.
Previously, the desirable optically resolved pyrazine compounds were obtained by later-stage resolution using D-(xe2x88x92) or L-(+)-tartaric acid, as disclosed in European Patent No. 569387. The present method has the advantage of minimizing material losses incurred by conducting resolutions after a multistep synthetic sequence, and results in a more efficient, higher-yielding process for preparing the (7S,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido(1,2-a)pyrazines.
The present invention relates to a process for separating a racemic mixture, or an optically enriched mixture, of trans-7-(hydroxymethyl) octahydro-2H-pyrido(1,2-a)pyrazine containing a first enantiomer having the formula: 
and a second enantiomer having the formula: 
the process comprising:
reacting the racemic mixture, or the optically enriched mixture, with (+)-naproxen or (xe2x88x92)-naproxen to form, respectively, a diastereomeric mixture of the (+)- or (xe2x88x92)-naproxen salts of each of the enantiomers; separating each of the diastereomeric (+)- or (xe2x88x92)-naproxen salts; and if desired, converting the respective naproxen salt of each enantiomer to the free base thereof.
The present invention further provides a salt of a compound with a substance selected from the group consisting of (+)-naproxen and (xe2x88x92)-naproxen, said compound having the formula 
The present invention also provides a salt of a compound compound with a substance selected from the group consisting of (+)-naproxen and (xe2x88x92)-naproxen, said compound having the formula 